Effect of Perlecan/Hspg2 Endoplasmic Reticulum Retention on Cellular Stress During Cartilage Development

Perlecan/Hspg2 (PLN) is a scaffolding proteoglycan functioning mainly in the extracellular matrix as a modulator of growth factor bioavailability. PLN gene loss‐of‐function mutation results in severe skeletal defects and embryonic death. In this study, we use a viable hypomorph mouse model in which PLN expression is reduced. Adult PLN hypomorph mice display a short stature, early osteoarthritis, and altered bone properties. These defects are likely the result of aberrant PLN expression during embryogenesis. Immunostaining of newborn cryosections revealed an absence of columnar organization and severe reduction of PLN secretion in the cartilage matrix of hypomorph versus control bones. Furthermore, the majority of PLN in the hypomorphs co‐localized with a strong signal for BiP, an endoplasmic reticulum (ER) chaperone involved in the early steps of the unfolding protein response (UPR). Interestingly, the retention of PLN in the ER was accompanied by increased deposition of another proteoglycan, aggrecan, in the cartilage matrix. Our data suggest that reduced PLN secretion during bone formation induces abnormal patterning that may be partially compensated by increased secretion of other matrix components. Ongoing work further investigates how the UPR and other cellular mechanisms contribute to the abnormal phenotype in PLN hypomorphs. Supported by NIH P20‐RR016458 and HHMI funds. Grant Funding Source : NIH P20 ‐ RR016458